Use of 5ht4 receptor antagonists in the prophylaxis or treatment of certain cardiovascular conditions

Abstract

The invention relates to the use of a 5-HT 4 receptor antagonist in the manufacture of a medicament for the prophylaxis or treatment of atrial remodelling in a mammal. Preferably, the antagonist is N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof. The invention also relates to the use of SB 207266 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of atrial fibrillation in a mammal by administering to the mammal a daily oral or parenteral dosage regimen of about 0.2 mg to 1.0 mg of the SB 207266 or salt thereof per kg of total body weight (measured as the free base). The invention also relates to the use of SB 207266 or a pharmaceutically acceptable salt thereof in the prophylaxis or treatment of atrial arrhythmia in a mammal by administration of the SB 207266 or salt thereof on the first day at a loading dose of about 1.2 to about 2.0 times the daily maintenance dose, followed by administration of the SB 207266 or salt at the daily maintenance dose on subsequent days.

1 . A pharmaceutical composition for human oral administration, being a tablet, troche or lozenge or having been placed in a hard gelatin capsule in powder or pellet form, wherein the composition comprises N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or a pharmaceutically acceptable salt thereof in a dose of from 50 mg to less than about 120 mg, measured as the free base, in combination with a pharmaceutically acceptable solid carrier. 
     
     
         2 . A composition as claimed in  claim 1 , wherein the N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the salt thereof is present in a dose of from 50 mg to 80 mg, measured as the free base. 
     
     
         3 . A composition as claimed in  claim 1 , wherein the N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the salt thereof is present in a dose of 50 mg or 80 mg, measured as the free base. 
     
     
         4 . A composition as claimed in  claim 1 , wherein the N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the salt thereof is present in a dose of 80 mg, measured as the free base. 
     
     
         5 . A pharmaceutical composition as claimed in  claim 1 , wherein the N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the salt thereof is the hydrochloride salt of N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide. 
     
     
         6 . A pharmaceutical composition as claimed in  claim 4 , wherein the N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the salt thereof is the hydrochloride salt of N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide. 
     
     
         7 . A pharmaceutical composition as claimed in  claim 4 , wherein the composition is adapted for use in a daily dosage regimen comprising oral administration to a human of 80 mg of the N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or the salt thereof, measured as the free base, given as a single dose once daily. 
     
     
         8 . A composition as claimed in  claim 1 , and being a tablet. 
     
     
         9 . A composition as claimed in  claim 4 , and being a tablet. 
     
     
         10 . A method of treatment or prophylaxis of atrial fibrillation in a human in need thereof, which comprises administering to said human a daily oral dosage regimen of 80 mg of N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or a pharmaceutically acceptable salt thereof, measured as the free base. 
     
     
         11 . A method as claimed in  claim 10 , wherein the human is a sufferer of or susceptible to persistent atrial fibrillation. 
     
     
         12 . A method as claimed in  claim 11 , which is a method of prophylaxis of persistent atrial fibrillation in the human in need thereof. 
     
     
         13 . A method of treatment or prophylaxis of electrical atrial remodelling, in a human in need thereof, which comprises administering to said human a daily oral dosage regimen of 80 mg of N-[(1- n butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide or a pharmaceutically acceptable salt thereof, measured as the free base. 
     
     
         14 . A method as claimed in  claim 13 , wherein the electrical atrial remodelling in the human includes shortening of the atrial effective refractory period. 
     
     
         15 . A method as claimed in  claim 13 , which is a method of treatment of electrical atrial remodelling in the human in need thereof.